Hepatoid tumors are a group of malignancies with histological features resembling
those of hepatocellular carcinoma (HCC). These rare tumors are most often found to
arise in abdominal or pelvic organs. Gross and microscopic pathological features include
neoplastic cells proliferating in a trabecular or sheetlike fashion with abundant,
eosinophilic cytoplasm. A solid pattern of cellular arrangement with sinusoid-like
spaces lined by endothelium is observed and shared with the HCC.[1] Presence of an extrahepatic primary tumor whose morphology is highly consistent
with HCC and immunohistochemistry positive for α-fetoprotein (AFP), in the absence
of a liver primary or other extrahepatic disease, is consistent with a hepatoid malignancy.[2]
CASE REPORT
A 45-year-old man presented to an otolaryngologist at another center with a history
of “sinus headaches” and retro-orbital pain. Past medical history was significant
for controlled hypertension. He was a nondrinker and had a remote history of a few
pack-years of smoking as a teenager. On examination, he was found to have a nasopharyngeal
mass and facial hypesthesia in the V1 and V2 distributions; however, there was no
palpable cervical lymphadenopathy. Computed tomography (CT) of the head and neck revealed
a T4N0, destructive left ethmoidosphenoidal mass invading the maxillary sinus, pterygopalatine
fossa, infratemporal fossa, and left cavernous sinus. Magnetic resonance imaging (MRI)
of the paranasal sinuses and skull base demonstrated a 5.7 × 4.4-cm mass compressing
the left orbit and optic nerve, with invasion of the anterior and middle cranial fossa
with encroachment on the medial aspect of the left temporal lobe (Fig. [1]). Chest, abdomen, and pelvis CT were negative for distant metastases. Laboratory
investigations revealed normal liver enzymes and liver function tests, as well as
normal serum AFP of 2 μg/L (normal range = 0 to 9) and normal carcinoembryonic antigen
(CEA) of 1 μg/L (normal range = 0 to 4.9).
Figure 1 Prechemoradiotherapy T1-weighted fat-saturated magnetic resonance images: axial (A)
and coronal (B, C).
Biopsy of the nasopharyngeal mass was performed; the initial diagnosis was squamous
cell carcinoma, and the patient was referred to our center for second opinion and
a radiation oncology consultation. At our center, an extensive immunopanel was performed
on the specimen and reviewed by two pathologists.
The histological slides demonstrated a solid trabecular proliferation of cells, supported
by a delicate capillary vascular frame, invading fibroconnective tissue and bone.
The neoplastic cells were medium to large and relatively monotonous, with medium to
abundant, clear and vacuolated pale eosinophilic cytoplasm. The nuclei were round
and reveal open, lacey chromatin with conspicuous eosinophilic nucleoli (Fig. [2A]). Frequent mitotic figures were present, with an absence of necrosis. On immunohistochemistry,
the tumor stained positive for epithelial membrane antigen and periodic acid-Schiff
(glycogen), cytokeratin (CK)8/18/19 (Fig. [2B]), S100 (Fig. [2C]), and AFP (Fig. [2D]), focally.
Figure 2 (A) Histological appearance. The tumor is composed of medium to large, monotonous
cells with abundant clear and vacuolated pale eosinophilic cytoplasm, with round nuclei
containing open lacey chromatin (hematoxylin and eosin staining, original magnification
400 × ). (B) The tumor stains diffusely for cytokeratin 8/18/19 (immunohistochemistry,
original magnification 400 × ). (C) The tumor stains focally for S100 (immunohistochemistry,
original magnification 400 × ). (D) The tumor stains focally for α-fetoprotein (immunohistochemistry,
original magnification 400 × ).
Stains for CK5/6 and p65 (squamous cell markers); CK7, CK20, thyroid transcription
factor-1, and CDX-2 (lung and gastrointestinal tract markers); smooth muscle actin
and calponin (myoepithelial markers); GCDFP-15 (breast marker); prostate-specific
antigen (prostate marker); CD10, CD30, RCC (renal cell carcinoma markers); hepatocyte
and A1AT (HCC markers); inhibin (adrenal cortical marker); synaptophysin, chromogranin,
(neuroendocrine markers); CEA (mono- and polyclonal), placental alkaline phosphatase
(germ cell marker), vimentin, follicule-stimulating hormone, luetinizing hormone,
adrenocorticotropic hormone, Melan-A, CD56, and Alcian blue pH 2.5 were negative.
The histo- and cytomorphological features are very similar to HCC and a final diagnosis
of undifferentiated adenocarcinoma with hepatoid morphology was made.
The case was reviewed at our multidisciplinary tumor board, and the patient underwent
induction chemotherapy with docetaxel/cisplatin/5-fluorouracil, followed by radiotherapy,
70 Gy in 35 fractions. Follow-up MRI of the paranasal sinuses and skull base revealed
greatly diminished tumor bulk with persistence of disease in the sphenoethmoidal sinuses,
along the skull base and left middle cranial fossa, with diminished enhancement of
the orbits (Fig. [3]). The patient received sorafenib maintenance therapy, and follow-up positron emission
tomography revealed no evidence of metabolically active neoplastic disease.
Figure 3 Postchemoradiotherapy, prior to sorafenib maintenance therapy; postgadolinium T1-weighted
magnetic resonance coronal image. The large tumor has decreased in size and demonstrates
extensive, coarse calcifications.
DISCUSSION
This is the first reported case of a primary skull base/nasopharyngeal hepatoid adenocarcinoma
(HAC). Hepatoid differentiation is a feature that has been described previously in
yolk sac tumors of the skull base; however, it has been absent in descriptions of
non–germ-cell origin of the skull base and the head and neck. Although two of the
most common locations of HAC include the stomach[3]
[4]
[5] and ovary,[6]
[7] multiple reports of tumors of non–germ-cell origin have been reported in the colon,
duodenum, gallbladder,[8] kidney, lower esophagus, lung,[9] pancreas,[10]
[11] rectum, urinary bladder,[12] uterine cervix,[13] and uterus.[14] Additionally, review of the literature revealed one case of HAC localized to shoulder
soft tissue.[15] The majority of HAC occur in middle-aged to elderly individuals.[10]
Microscopic descriptions of HAC in other sites such as the lung, pancreas, and gallbladder
have included a heterogeneous tubular proliferative pattern with large neoplastic
cells containing abundant, eosinophilic cytoplasm with centrally positioned nuclei
and an overall monotonous appearance analogous to HCC.[1]
[8]
[9] The features in our case are congruent with these descriptions.
CT features of HAC in other anatomic locations have included heterogeneously appearing
tumors with a density similar to liver tissue, demonstrating moderate enhancement
post–intravenous iodine contrast.[16] In our case, the large tumor had extensively eroded surrounding bone and significantly
infiltrated the left orbit, cavernous sinus, sella turcica, and anterior and middle
cranial fossae. This aggressive behavior is consistent with HAC, a rare extrahepatic
neoplasm, known to invade adjacent tissue.[14]
Our patient's serum AFP was normal. Although the majority of HACs produce AFP, up
to one-third have a normal serum level.[15] Additionally, it has been suggested a diagnosis of HAC should depend on the histopathologic
features rather than AFP production, as HAC has been shown to display similar biological
behavior regardless of AFP production.[5]
Extensive clinical, biochemical, and radiological metastatic workup excluded another
possible primary origin. Moreover, the aforementioned staining pattern refuted distant
metastases from squamous, lung, gastrointestinal, hepatic, renal, pancreatic, germ
cell, adrenal, neuroendocrine, or salivary gland origin. Accordingly, having excluded
other possible primary tumors and given the histo- and cytomorphological resemblance
between our patient's nasopharyngeal/skull base tumor and HCC, the case was classified
appropriately as a HAC arising from the skull base.
